We propose a pilot project where we exploit new whole genome sequencing technologies to identify important DNA sequence variants in the nematode Caenorhabditis elegans. In so doing, we open the door to the creation of an immensely powerful and technologically enabling genetic resource. The project will go far beyond simply addressing the needs of the research community for mutant C. elegans strains. It will create opportunities for new, unique reverse and forward genetics screens that include the identification of bioactive, drug-like compounds and their target pathways - a major component of the NIH roadmap to promote translational research. Moreover, a sufficiently large collection with multiple alleles per gene will allow investigators to identify directly the gene(s) responsible for a given screening phenotype. Further, by setting the stage for other powerful genome-wide initiatives like a comprehensive expression profile for every strain in the collection we provide the means to identify correlations between gene function and expression that could not be discovered in any other way. The mutant strain collection also will provide new opportunities for the analysis of quantitative traits, one of the most pressing and significant frontiers in the understanding of human biology and disease. Finally, the genotype-phenotype correlations that emerge from the convergence of the sequenced strain collection, new high-throughput microfluidic phenotyping platforms, and powerful new theoretical frameworks founded on networks will lead to extraordinary new biological knowledge. The proposed project, therefore, will form the basis for a significant, high-profile, unique research initiative that will lead to a deeper level of understanding of normal human biology and disease. PUBLIC HEALTH RELEVANCE: This work will set the stage for powerful new genetic studies of the model system Caenorhabditis elegans and will lead to a deeper understanding of gene function in both health and disease. Further, it will provide new tools to identify drug targets and their associated genetic pathways.